Antigen-specific peptide immunotherapy for treatment and prevention of type 1 diabetes

Abstract

Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing pancreatic β cells, involving CD4 + and CD8 + T cells. Currently, there is no treatment for T1D, and disease management relies on insulin replacement therapy associated with major complications. Therefore, there is an urgent need for an effective T1D therapy without the need for systemic immunosuppression. The ideal immunotherapy would be safe, cheap and specifically inactivate or eliminate pathogenic islet-specific T cells and/or increase isletspecific regulatory T cells (Tregs). To this end, I have investigated the utility of liposome delivered antigen-specific therapy for T1D. Using the non-obese diabetic (NOD) mouse model of T1D, the Hamilton-Williams lab has shown previously that liposomes co-encapsulating a CD4-targeted islet antigen and NF-kB inhibitor induced antigen-specific induction of regulatory CD4 + T cells in mice and delay disease progression. As islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is a major CD8-T cells diabetogenic antigen in NOD mice, I now aimed to test the efficacy of an IGRP-specific immunotherapy targeting CD8+ T cells for inducing tolerance and protecting from disease. For this current model, I have used liposomes co-delivering the CD8 epitope IGRP206-214 and NF-kB inhibitor calcitriol to treat NOD mice. Liposome delivered peptide was presented by antigen-presenting cells to T cells as IGRP-specific CD8 + transgenic 8.3 T cells proliferated in draining lymph nodes after treatment. IGRP-specific 8.3 T cells expanded at day 4 and then contracted by day 10 following delivery of IGRP206-214 only and IGRP206-214 /D3 liposomes. Furthermore, the upregulation of activation and anergy markers such as CD44, LAG-3 and PD-1 on the 8.3 T cells following the liposomal treatment was observed. In contrast, endogenous IGRP-specific CD8 + population did not increase in frequency or upregulate of activation markers after one liposomal treatment. However, after two treatments the endogenous IGRP-specific cells significantly upregulated CD44 and PD-1. Consistent with the cells gaining a tolerogenic phenotype, IFN-g production was suppressed in endogenous IGRP-specific CD8 + T cells following IGRP206-214 /D3 but not IGRP206-214 only liposome treatment. These data suggest that endogenous IGRP-specific CD8 + T cells get activated in response to the liposome delivered antigen, but they gain an unresponsive phenotype. I then tested the efficacy of the therapy firstly using an accelerated transfer model of diabetes. IGRP206-214/D3 subcutaneous liposomal treatment significantly delayed the Publications during candidature Research papers